Mutsuyoshi Matsushita

PHARMACOLOGICAL PROFILE OF JTE-522, A NOVEL PROSTAGLANDIN H SYNTHASE-2 INHIBITOR, IN RATS

Abstract.Objective and Design: The antinociceptive, antipyretic, and anti-inflammatory effects of JTE-522, a novel selective prostaglandin H synthase (PGHS)-2 inhibitor, were examined in rats.¶Materials: Sheep seminal vesicle PGHS-1 and placenta PGHS-2 were used for in vitro assay, while for in vivo experiments, male rats (4–8 weeks old) were used.¶Treatment: JTE-522 and reference compounds (0.01–100 μM) were subjected to enzyme assay. JTE-522 (0.3–30 mg/kg) and indomethacin (0.3–10 mg/kg) were administered orally.¶Results: JTE-522 inhibited PGHS-2 (IC50: 0.64 μM) without affecting PGHS-1 activity at 100 μM. In rats with yeast-induced hyperalgesia, JTE-522 showed a dose-dependent antinociceptive effect (ED50: 4.4 mg/kg). In rats with yeast-induced pyrexia, JTE-522 significantly reversed the pyrexic response (ED50: 3.9 mg/kg). Orally administered JTE-522 dose-dependently inhibited carrageenin-induced rat paw edema (ED30: 4.7 mg/kg). In rats with adjuvant-induced arthritis, JTE-522 showed a significant inhibitory effect at daily doses of 0.3–3 mg/kg. JTE-522 did not cause severe gastric lesions at oral doses up to 300 mg/kg.¶Conclusions: Our results indicate that the selective PGHS-2 inhibitor JTE-522 may represent a novel type of anti-inflammatory drug without adverse effects on the gastrointestinal tract. JTE-522 may thus be a promising agent for treating both acute inflammatory diseases and chronic inflammatory diseases such as rheumatoid arthritis.

JTE-522 selectively inhibits cyclooxygenase-2-derived prostaglandin production in inflammatory tissues.

Abstract.Objective and Design: To investigate the effect of JTE-522, a selective cyclooxygenase (COX)-2 inhibitor, on prostaglandin (PG) production and COX expression in rats.¶Subjects: Male rats (4-8 weeks old) were used for in vivo experiments, while for in vitro assay, rat peritoneal macrophages were used.¶Treatment: JTE-522 (1-100mg/kg) and indomethacin (0.03-10mg/kg) were administered orally. JTE-522 and reference compounds (0.01-10 μM) were subjected to COX expression.¶Results: JTE-522 inhibited the development of carrageenin-induced paw edema and PGE2 production in inflammatory paws at a dose of 10mg/kg. On the other hand, JTE-522 (1-100 mg/kg) did not affect A23187-stimulated thromboxane B2 release from whole blood or the PGE2 level in gastric mucosa. JTE-522 did not suppress lipopolysaccharide-induced COX-2 expression in peritoneal macrophages.¶Conclusion: These results indicate that JTE-522 selectively inhibits PG production mediated by COX-2 in inflammatory tissues. JTE-522 may thus represent a novel type of anti-inflammatory drug without adverse effects on the gastrointestinal tract.

Preventive effects of glycaemic control on ocular complications of Spontaneously Diabetic Torii rat.

Aim:  Spontaneously Diabetic Torii (SDT) rat is a new model of non‐obese type 2 diabetes. SDT rats show severe ocular complications such as cataracts, tractional retinal detachment with fibrous proliferation and massive haemorrhaging in the anterior chamber. In the present study, blood glucose levels of SDT rats were controlled in order to examine whether these ocular complications are caused by hyperglycaemia.

JTP-426467 acts as a selective antagonist for peroxisome proliferator-activated receptor γin vitro and in vivo

Aim:  JTP‐426467 was identified as a result of screening in search of selective antagonist for peroxisome proliferator‐activated receptor γ (PPARγ). We examined whether JTP‐426467 functioned as a PPARγ antagonist in vitro and in vivo and investigated physiological effects of JTP‐426467.

Ferric Citrate Hydrate, a New Phosphate Binder, Prevents the Complications of Secondary Hyperparathyroidism and Vascular Calcification

Background/Aims: Ferric citrate hydrate (JTT-751) is being developed as a treatment for hyperphosphatemia in chronic kidney disease patients, and shows serum phosphorus-reducing effects on hyperphosphatemia in hemodialysis patients. We examined whether JTT-751 could reduce phosphorus absorption in normal rats and prevent the progression of ectopic calcification, secondary hyperparathyroidism and bone abnormalities in chronic renal failure (CRF) rats. Methods: Normal rats were fed a diet containing 0.3, 1 or 3% JTT-751 for 7 days. The effects of JTT-751 on phosphorus absorption were evaluated with fecal and urinary phosphorus excretion. Next, a CRF model simulating hyperphosphatemia was induced by feeding rats a 0.75% adenine diet. After 21 days of starting the adenine diet feeding, 1 or 3% JTT-751 was administered for 35 days by dietary admixture. The serum phosphorus levels and mineral parameters were measured. Calcification in the aorta was examined biochemically and histopathologically. Hyperparathyroidism and bone abnormalities were evaluated by histopathological analysis of the parathyroid and femur, respectively. Results: In normal rats, JTT-751 increased fecal phosphorus excretion and reduced phosphorus absorption and urinary phosphorus excretion. In CRF rats, JTT-751 reduced serum phosphorus levels, the calcium-phosphorus product and calcium content in the aorta. Serum intact parathyroid hormone levels and the incidence and severity of parathyroid hyperplasia were also decreased. JTT-751 reduced femoral bone fibrosis, porosity and osteoid formation. Conclusions: JTT-751 could bind with phosphate in the gastrointestinal tract, increase fecal phosphorus excretion and reduce phosphorus absorption. JTT-751 could prevent the progression of ectopic calcification, secondary hyperparathyroidism and bone abnormalities in rats.

Pharmacological profiles of a novel protein tyrosine phosphatase 1B inhibitor, JTT-551

Aim: Protein tyrosine phosphatase 1B (PTP1B), a negative regulator of insulin signalling, is a novel therapeutic target for type 2 diabetes mellitus. We evaluated in vitro and in vivo the pharmacological profiles of a new PTP1B inhibitor, JTT‐551: monosodium ({[5‐(1,1‐dimethylethyl)thiazol‐2‐yl]methyl} {[(4‐{4‐[4‐(1‐propylbutyl)phenoxy]methyl}phenyl)thiazol‐2‐yl]methyl}amino)acetate.

Novel protein kinase C‐β isoform selective inhibitor JTT‐010 ameliorates both hyper‐ and hypoalgesia in streptozotocin‐ induced diabetic rats

Aim:  Activation of protein kinase C (PKC) is thought to play an important role in the pathogenesis of diabetic microvascular complications. PKC‐β is elevated in hyperglycaemic conditions, both in vivo and in vitro. In this study, pharmacological effects of a novel PKC‐β isoform selective inhibitor, JTT‐010 ((2R)‐3‐(2‐aminomethyl‐2,3‐dihydro‐1H‐3a‐azacyclopenta(a)inden‐8‐yl)‐4‐phenylaminopyrrole‐2,5‐dione monomethanesulphonate), on diabetic neuropathy were examined.

Hereditary postprandial hypertriglyceridemic rabbit exhibits insulin resistance and central obesity: a novel model of metabolic syndrome.

Objective—We have established a hereditary postprandial hypertriglyceridemic (PHT) rabbit. The present study was designed to define whether this rabbit model represents both insulin resistance and central obesity. Methods and Results—Body weight, abdominal circumference, visceral fat weight, and glucose tolerance were compared between PHT and Japanese white (JW) rabbit. Plasma levels of triglycerides (TG), total cholesterol (TC), glucose, and insulin were measured before and after feeding. Abdominal circumference of PHT rabbit was larger than that of JW rabbit, with no difference in body mass index. Visceral fat accumulation was noted as obvious in mesenterium, retroperitoneal space, and epididymal area. Plasma TG and TC levels were high preprandially and markedly increased postprandially in PHT rabbit compared with JW rabbit. Although plasma glucose levels were comparable in both groups, plasma insulin levels were elevated in PHT rabbit. Glucose tolerance tests indicated that plasma insulin levels in PHT rabbit were consistently higher than in JW rabbit. A positive correlation was observed between plasma insulin levels and visceral fat weight in PHT rabbit. Conclusions—PHT rabbit shows insulin resistance along with central obesity. PHT rabbit will serve as a model for elucidating genetic predisposition and pathophysiology in metabolic syndrome.

Protein kinase C beta inhibitor prevents diabetic peripheral neuropathy, but not histopathological abnormalities of retina in Spontaneously Diabetic Torii rat

Spontaneously Diabetic Torii (SDT) rat shows severe ocular complications such as tractional retinal detachment. In the present study, effect of protein kinase C beta (PKCβ) inhibitor JTT‐010 was evaluated to clarify the involvement of PKCβ in complications of SDT rat. SDT rats were administered JTT‐010 (10 or 50 mg/kg/day) for 48 weeks. SDT rats showed delayed oscillatory potentials in electroretinogram. Delayed motor nerve conduction velocity, decreased coefficients of variation of R–R intervals in electrocardiogram and thermal hypoalgesia were also observed. These functional disorders were prevented by administration of JTT‐010. Abnormal retinal vascular was formed and the optic disc was protruded in SDT rat; however, JTT‐010 did not prevent these hyperglycaemia‐induced retinal abnormalities. These findings indicate that PKCβ is intimately involved in diabetic complications; however, it seems that other factor(s) are primary contributors to histopathological abnormalities in retina. Therefore, PKCβ inhibitors require concurrent administration of antihyperglycaemic drugs to achieve maximum effect on diabetic complications.

A high-fat diet inhibits the progression of diabetes mellitus in type 2 diabetic rats

It is well known that rats and mice, when fed a high-fat diet, develop obesity associated with abnormal glycolipid metabolism. In this study, we investigated the effects of a high-fat diet on a diabetic rat model, Spontaneously Diabetic Torii (SDT), which develops diabetes due to decreased insulin production and secretion with age. We hypothesized that a high-fat diet would accelerate the induction of diabetes in this model. The SDT rats were divided into 2 groups, which were fed a high-fat diet or standard diet for 16 weeks. The group fed a high-fat diet developed obesity, hyperinsulinemia, and hyperlipidemia until 16 weeks of age. Before 16 weeks of age, hyperglycemia accompanied by hypoinsulinemia developed in the group on a standard diet, but serum glucose levels were comparable in both groups. After 16 weeks of age, the group on a standard diet showed an increase in serum glucose levels and a decrease in serum insulin levels. Unexpectedly, in the group on the high-fat diet, we observed a suppressed of the progression of hyperglycemia/hypoinsulinemia. Histopathological observation revealed more pancreatic beta cells in the group on the high-fat diet. This study suggests that feeding SDT rats a high-fat diet induces obesity, hyperinsulinemia, and hyperlipidemia, but not hyperglycemia, until 16 weeks of age. Thereafter, age-dependent progress of hyperglycemia and hypoinsulinemia was delayed by a high-fat diet. The hyperfunction of pancreatic beta cells induced by a high-fat diet before the onset of hyperglycemia appears to suppress development of hyperglycemia/hypoinsulinemia.